RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites

Frédérick A. Mallette, Francesca Mattiroli, Gaofeng Cui, Leah C. Young, Michael J. Hendzel, Georges Mer, Titia K. Sixma, Stéphane Richard

Research output: Contribution to journalArticle

218 Scopus citations

Abstract

In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8-dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8- and RNF168-deficient cells to form 53BP1 foci. We propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites.

Original languageEnglish (US)
Pages (from-to)1865-1878
Number of pages14
JournalEMBO Journal
Volume31
Issue number8
DOIs
StatePublished - Apr 18 2012

Keywords

  • 53BP1
  • JMJD2A
  • RNF168
  • RNF8
  • tudor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Mallette, F. A., Mattiroli, F., Cui, G., Young, L. C., Hendzel, M. J., Mer, G., Sixma, T. K., & Richard, S. (2012). RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO Journal, 31(8), 1865-1878. https://doi.org/10.1038/emboj.2012.47